EP1874268A1 - Injectable depot formulations and methods for providing sustained release of nanoparticle compositions - Google Patents

Injectable depot formulations and methods for providing sustained release of nanoparticle compositions

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Publication number
EP1874268A1
EP1874268A1 EP06744618A EP06744618A EP1874268A1 EP 1874268 A1 EP1874268 A1 EP 1874268A1 EP 06744618 A EP06744618 A EP 06744618A EP 06744618 A EP06744618 A EP 06744618A EP 1874268 A1 EP1874268 A1 EP 1874268A1
Authority
EP
European Patent Office
Prior art keywords
formulation
surface stabilizer
weight
another embodiment
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06744618A
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German (de)
English (en)
French (fr)
Inventor
Jaymin Chandrakant Shah
Parang Suresh Shah
Dawn Renee Wagner
Peter Wisniecki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Products Inc
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Pfizer Products Inc
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Publication date
Application filed by Pfizer Products Inc filed Critical Pfizer Products Inc
Publication of EP1874268A1 publication Critical patent/EP1874268A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82B—NANOSTRUCTURES FORMED BY MANIPULATION OF INDIVIDUAL ATOMS, MOLECULES, OR LIMITED COLLECTIONS OF ATOMS OR MOLECULES AS DISCRETE UNITS; MANUFACTURE OR TREATMENT THEREOF
    • B82B1/00—Nanostructures formed by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to pharmaceutically active compounds.
  • the present invention particularly relates to ziprasidone, including nanoparticles of ziprasidone, especially nanoparticles comprising one or more surface stabilizers, and formulations comprising nanoparticles of ziprasidone.
  • the present invention comprises a pharmaceutical formulation comprising: a compound selected from the group consisting of ziprasidone, having a maximum average particle size; a carrier; and optionally a surface stabilizer, for example at least two surface stabilizers.
  • the present invention also comprises methods of treating psychosis with such a formulation and processes for making such a formulation.
  • Ziprasidone has utility as a neuroleptic, and is thus useful, inter alia, as an antipsychotic.
  • ziprasidone is approved for administration twice daily in the form of an immediate release (IR) capsule for acute and long term treatment of schizophrenia and for mania.
  • IR immediate release
  • ziprasidone may be administered in intramuscular immediate release (IR) injection form for acute control of agitation in schizophrenic patients.
  • Atypical antipsychotics such as ziprasidone are associated with lower incidence of side effects, particularly extrapyramidal symptoms (EPS), excessive or prolonged sedation, and nonresponsiveness, with greater efficacy in treatment- refractory patients.
  • EPS extrapyramidal symptoms
  • These beneficial attributes are thought to be related to the antagonism of both D 2 and 5HT 2A receptors which is characteristic of atypical antipsychotics.
  • one major problem associated with the long-term treatment of schizophrenics is noncompliance with medication. Indeed, it is conventionally thought that substantial numbers of schizophrenic patients are not or only partially compliant with their medication. Poor compliance can cause relapse into the psychotic condition thereby negating whatever benefits were achieved through treatment in the first place.
  • depot formulation which, inter alia, may be administered via intramuscular or subcutaneous injection.
  • a depot formulation is specially formulated to provide slow absorption of the drug from the site of administration, often keeping therapeutic levels of the drug in the patient's system for days or weeks at a time.
  • depot formulations comprising antipsychotic drugs can be useful in increasing patient compliance among schizophrenics.
  • U.S. Patent No. 6,555, 544 (granted April 29, 2003) describes a depot formulation of 9-hydroxyrisperidone.
  • U.S. Patent No. 6,232, 304 (granted May 15, 2001 ) describes a ziprasidone salt solubilized with cyclodextrins for an immediate release intramuscular injection formulation.
  • U.S. Patent No. 6,150, 366 (granted November 21 , 2000) describes a pharmaceutical composition describing crystalline ziprasidone and a carrier.
  • U.S. Patent No. 6, 267, 989 (granted July 31 , 2001) describes a water- insoluble crystalline drug to which a surface modifier is adsorbed in an amount sufficient to maintain a defined particle size.
  • WO 00/18374 (filed October 1, 1999) describes a controlled release nanoparticle composition.
  • WO 00/09096 (filed August 12, 1999) describes an injectable nanoparticle formulation of naproxen. Accordingly, a need still exists for new drug therapies for the treatment of subjects suffering from or susceptible to psychosis - particularly, a long acting form of an atypical antipsychotic providing a suitable therapy that minimizes side effects while enhancing patient compliance through a reduced dosing regimen.
  • ziprasidone is poorly soluble.
  • a nanoparticle depot formulation of ziprasidone may reduce overall exposure to ziprasidone compared to the oral capsules while providing sufficient exposure to ensure efficacy.
  • the present invention relates to a pharmaceutical formulation comprising ziprasidone or a pharmaceutically acceptable salt thereof suitable for use as a depot formulation for administration via intramuscular or subcutaneous injection.
  • the ziprasidone or ziprasidone salt in the formulation has a maximum average particle size.
  • the invention comprises a pharmaceutical formulation comprising (1) a pharmaceutically acceptable amount of a compound selected from ziprasidone and a pharmaceutically acceptable salt of ziprasidone, which compound has a maximum average particle size, and (2) a pharmaceutically acceptable carrier.
  • the formulation comprises (1) a pharmaceutically effective amount of a compound selected from the group ziprasidoneand a pharmaceutically acceptable salt thereof, which compound has a maximum average particle size; (2) a pharmaceutically acceptable carrier; and (3) at least one surface stabilizer.
  • the formulation consists of at least two surface stabilizers.
  • the formulations of the invention may, for example, comprise from one to ten surface stabilizers, preferably two to five stabilizers.
  • the formulation consists of two -A-
  • the formulation consists of two surface stabilizers and a bulking agent.
  • the present invention comprises processes for preparing such a formulation.
  • the present invention comprises the use of such a composition as a medicament in the treatment of psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioral disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioral disturbances in mental retardation and autism, Tourette's syndrome, bipolar disorder (for example bipolar mania, bipolar depression, or for effecting mood stabilization in bipolar disorder), depression and anxiety.
  • the present invention comprises methods of treating psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioral disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioral disturbances in mental retardation and autism, Tourette's syndrome, bipolar disorder (for example bipolar mania, bipolar depression, or for effecting mood stabilization in bipolar disorder), depression and anxiety.
  • the invention relates to nanoparticles of ziprasidone or nanoparticles of a pharmaceutically acceptable salt of ziprasidone.
  • the nanoparticles of ziprasidone or nanoparticles of a pharmaceutically acceptable ziprasidone salt comprise a surface stabilizer.
  • the nanoparticles of ziprasidone or nanoparticles of a pharmaceutically acceptable ziprasidone salt comprise at least two surface stabilizers.
  • the term "compound” refers to a form of a therapeutic or diagnostic agent which is a component of an injectable depot formulation.
  • the compound may be a pharmaceutical, including, without limitation, biologies such as proteins, peptides and nucleic acids or a diagnostic, including, without limitation, contrast agents.
  • the compound is crystalline.
  • the compound is amorphous.
  • the compound is a mixture of crystalline and amorphous forms.
  • the compound is ziprasidone.
  • the compound is selected from the group
  • ziprasidone free base and a pharmaceutically acceptable salt of ziprasidone.
  • the ziprasidone may be crystalline, amorphous, or a mixture of crystalline and amorphous.
  • the compound has low aqueous solubility.
  • Ziprasidone is a poorly water soluble drug, i.e. it has low aqueous solubility.
  • the logP of the compound is at least about 3 or greater.
  • the compound has a high melting point. ' A high melting compound is one with a melting point greater than about 130 degrees Celsius.
  • surface stabilizer refers to a molecule that: (1) is adsorbed on the surface of a compound; (2) otherwise physically adheres to the surface of a compound; or (3) remains in solution with a compound, acting to maintain the effective particle size of the compound.
  • a surface stabilizer does not chemically react (i.e. form a covalent bond) with the drug substance (compound).
  • a surface stabilizer also does not necessarily form covalent crosslinkages with itself or other surface stabilizers in a formulation and/or when adsorbed onto compound surfaces.
  • a surface stabilizer on the surface of a compound or otherwise in a formulation of the invention is essentially free of covalent crosslinkages.
  • a first surface stabilizer is present in an amount sufficient to maintain an effective average particle size of the compound.
  • one or more surface stabilizers are present in an amount sufficient to maintain an effective particle size of the compound.
  • a surface stabilizer is a surfactant.
  • a surface stabilizer is a crystallization inhibitor.
  • surfactant refers to amphipathic molecules that consist of a non- polar hydrophobic portion, exemplified by a straight or branched hydrocarbon or fluorocarbon chain containing 8-18 carbon atoms, which is attached to a polar or ionic portion (hydrophilic).
  • the hydrophilic portion may be nonionic, ionic or zwitterionic and accompanied by counter ions.
  • surfactants anionic, cationic, amphoteric, nonionic and polymeric. In the case of nonionic and polymeric surfactants, a single surfactant may be properly classified as a member of both categories.
  • An exemplary group of surfactants that may be properly classified in this manner are the ethylene oxide-propylene oxide copolymers, referred to as Pluronics® (Wyandotte), Synperonic PE ®(ICI) and Poloxamers® (BASF). Polymers such as HPMC and PVP are sometimes classified as polymeric surfactants.
  • Exemplary classes of surfactants include, without limitation: carboxylates, sulphates, sulphonates, phosphates, sulphosuccinates, isethionates, taurates, quartemary ammonium compounds, N-alkyl betaines, N-alkyl amino propionates, alcohol ethoxylates, alkyl phenol ethoxylates, fatty acid ethoxylates, monoalkaolamide ethoxylates, sorbitan ester ethoxylates, fatty amine ethoxylates, ethylene oxide-propylene oxide co-polymers, glycerol esters, glycol esters, glucosides, sucrose esters, amino oxides, sulphinyl surfactants, polyoxyethylene allcyl ethers, polyoxyethylene alkyl ethers, polyglycolized glycerides, short-chain glyceryl mono-alkylates, alkyl ary
  • Exemplary surfactants include, without limitation: dodecyl hexaoxyethylene glycol monoether, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan mono-oleate, sorbitan tristearate, sorbitan trioleate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan mono-oleate, polyoxyethylene (20) sorbitan tristearate, polyoxyethylene (20) sorbitan trioleate, linolin, castor oil ethoxylates, Pluronic® F108, Pluronic® F68, Pluronic® F127, benzalkonium chloride, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxyprop
  • ethylene oxide-propylene oxide copolymers refers to four types of nonionic block copolymers, of which Pluronic® F108 is one, as described in Table A-2, immediately below:
  • Pluronic® F108 refers to poloxamer 338 and is the polyoxyethylene-polyoxypropylene block copolymer that conforms generally to the formula HO[CH 2 CH 2 O] n [CH(CH 3 )CH 2 O]JCH 2 CH 2 O] n H in which the average values of n, m and n are respectively 128, 54 and 128.
  • crystallization inhibitor refers to a polymer or other substances that can substantially inhibit precipitation and/or crystallization of a poorly water- soluble drug.
  • a polymeric surfactant is a crystallization inhibitor.
  • the crystallization inhibitor is a cellulosic or non- cellulosic polymer and is substantially water-soluble.
  • the crystallization inhibitor is HPMC.
  • a crystallization inhibitor is polyvinylpyrrolidone (PVP).
  • Table A-3 Method to Test Crystallization Inhibitors for Efficacy
  • Step i A suitable amount of the drug is dissolved in a solvent (e.g.. ethanol, dimethyl sulfoxide or, where the drug is an acid or base, water) to obtain a concentrated drug solution.
  • a solvent e.g.. ethanol, dimethyl sulfoxide or, where the drug is an acid or base, water
  • Step 2 A volume of water or buffered solution with a fixed pH is placed in a first vessel and maintained at room temperature.
  • a technician performing Test I will readily find a suitable polymer concentration for the test within the polymer concentration range provided above, by routine experimentation.
  • a concentration of the polymer is selected such that when Test I is performed, the apparent absorbance of the second sample solution is not greater than about 50% of the apparent absorbance of the first sample solution
  • the terms “logP” and “Partition Coefficient” refer to a measure of how well a substance partitions between a lipid (oil) and water.
  • the Partition Coefficient is also a very useful parameter which may be used in combination with the pKa to predict the distribution of a compound in a biological system. Factors such as absorption, excretion and penetration of the CNS may be related to the Log P value of a compound and in certain cases predictions made.
  • the terms “low aqueous solubility” and “poorly water soluble drug” refer to a therapeutic or diagnostic agent with a solubility in water of less than about 10 mg/mL In another embodiment, the solubility in water is less than about 1 mg/mL
  • particle size refers to effective diameter, in the longest dimension, of compound particles. Particle size is believed to be an important parameter affecting the clinical effectiveness of therapeutic or diagnostic agents of low aqueous solubility.
  • average particle size and “mean particle size” refer to compound particle size of which at least 50% or more of the compound particles are, when measured by dynamic light scattering.
  • an average particle size of from about 120 nm to about 400 nm means that at least 50% of the compound particles have a particle size from about 120 nm to about 400 nm when measured by standard techniques, as indicated in other embodiments herein.
  • at least 70% of the particles, by weight have a particle size of less than the indicated size.
  • at least 90% of the particles have the defined particle size.
  • at least 95% of the particles have the defined particle size.
  • at least 99% of the particles have the defined particle size.
  • different measurement techniques may be employed - such as laser diffraction.
  • the present invention comprises, in part, a novel injectable depot formulation of ziprasidone.
  • the present invention also comprises a method of treating psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioral disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioral disturbances in mental retardation and autism, Tourette's syndrome, bipolar disorder (for example bipolar mania, bipolar depression, or effecting mood stabilization in bipolar disorder), depression and anxiety in a patient in need thereof.
  • the present invention also comprises a process for synthesizing the ziprasidone nanoparticles used in the formulation as well as synthesizing the formulation itself.
  • an injectable depot formulation comprises: a) a pharmaceutically effective amount of a compound selected from the group consisting of ziprasidone and a pharmaceutically acceptable salt thereof, the compound in the form of nanoparticles having an average particle size of less than about 2000 nm; b) a pharmaceutically acceptable carrier; and c) at least two surface stabilizers; wherein at least one of the surface stabilizers is adsorbed on the surface of the nanoparticles; and wherein the combined amount of the surface stabilizers is effective to maintain the average particle size of the nanoparticles.
  • the invention provides an injectable depot formulation that comprises: a) a pharmaceutically effective amount of a compound selected from the group consisting of ziprasidone and a pharmaceutically acceptable salt thereof, the compound in the form of nanoparticles having an average particle size of less than about 2000 nm; and b)a pharmaceutically acceptable carrier.
  • the invention provides an injectable depot formulation that comprises: a) a pharmaceutically effective amount of a compound selected from the group consisting of ziprasidone and a pharmaceutically acceptable salt thereof, the compound in the form of nanoparticles having an average particle size of less than about 2000 nm; b)a pharmaceutically acceptable carrier; and c) a surface stabilizer in an amount effective to maintain the average particle size of the nanoparticles.
  • a pharmaceutically effective amount of a compound selected from the group consisting of ziprasidone and a pharmaceutically acceptable salt thereof the compound in the form of nanoparticles having an average particle size of less than about 2000 nm
  • a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable carrier
  • a surface stabilizer in an amount effective to maintain the average particle size of the nanoparticles.
  • at least two surface stabilizers are adsorbed on the surface of the nanoparticles.
  • At least three surface stabilizers are adsorbed on the surface of the nanoparticles.
  • Pharmaceutically acceptable salts are comprised of acid addition salts and base addition salts, as well as hemisalts.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, ste
  • Ziprasidone may also exist in unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanoi.
  • the term 'hydrate' is employed when said solvent is water.
  • a currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
  • channel hydrates the water molecules lie in lattice channels where they are next to other water molecules.
  • metal-ion coordinated hydrates the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well- defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • compositions of ziprasidone may be prepared by one or more of three methods:
  • the compound is ziprasidone free base. In still another embodiment, the compound is ziprasidone mesylate. In another embodiment, the compound is ziprasidone mesylate trihydrate. In still another embodiment, the compound is ziprasidone HCI. In another embodiment of the compound, the compound is crystalline. In still another embodiment, the compound is crystalline ziprasidone free base. In still another embodiment, the compound is crystalline ziprasidone mesylate. In still another embodiment, the compound is crystalline ziprasidone HCi. In another embodiment of the injectable depot formulation, the pharmaceutically acceptable carrier is water.
  • the nanoparticles of the compound have an average particle size of less than about 1500 nm. In still another embodiment, the nanoparticles have an average particle size of less than about 1000 nm. In still another embodiment, the nanoparticles have an average particle size of less than about 500 nm. In still another embodiment, the nanoparticles have an average particle size of less than about 350 nm.
  • the nanoparticles have an average particle size from about 120 nm to about 400 nm. In still another embodiment, the nanoparticles have an average particle size from about 220 nm to about 350 nm.
  • the nanoparticles have an average particle size of about 250 nm.
  • the compound is crystalline ziprasidone free base and the average particle size is about 250 nm.
  • nanoparticles have an average particle size of about 120 nm.
  • the compound is crystalline ziprasidone HCl and the average particle size is about 120 nm.
  • the nanoparticles have an average particle size of about 400 nm.
  • the compound is crystalline ziprasidone mesylate and the average particle size is about 400 nm.
  • the amount by weight of ziprasidone is less than about 60% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of ziprasidone is less than about 40% by weight of the total volume of the formulation.
  • the amount by weight of ziprasidone is at least about 15% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of ziprasdione is at least about 20% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of ziprasdione is at least about 40% by weight of the total volume of the formulation.
  • the amount by weight of ziprasidone is from about
  • the amount by weight is from about 20% by weight to about
  • the amount by weight is from about 15% by weight to about 40% by weight of the total volume of the formulation. In still another embodiment, the amount by weight is from about 20% by weight to about 40% by weight of the total volume of the formulation.
  • the amount by weight of the compound is about 21% by weight of the total volume of the formulation. In another embodiment of Formulation I-H, the amount by weight of the compound is about 23% by weight of the total volume of the formulation. In another embodiment of Formulation 1 -M, the amount by weight of the compound is about 28% by weight of the total volume of the formulation. In another embodiment of Formulation 1-F, the amount by weight of the compound is about 42% by weight of the total volume of the formulation.
  • a first surface stabilizer is a surfactant.
  • a first surface stabilizer is selected from the group consisting of anionic surfactants, cationic surfactants, amphoteric surfactants, non-ionic surfactants and polymeric surfactants.
  • a first surface stabilizer is an anionic surfactant. In another embodiment, a first surface stabilizer is a cationic surfactant. In another embodiment, a first surface stabilizer is an amphoteric surfactant. In another embodiment, a first surface stabilizer is a non- ionic surfactant. In another embodiment, a first surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer is a crystallization inhibitor.
  • a second surface stabilizer is selected from the group consisting of anionic surfactants, cationic surfactants, amphoteric surfactants, non-ionic surfactants and polymeric surfactants.
  • a second surface stabilizer is an anionic surfactant.
  • a second surface stabilizer is a cationic surfactant.
  • a second surface stabilizer is an amphoteric surfactant.
  • a second surface stabilizer is a non-ionic surfactant.
  • a second surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer and a second surface stabilizer are independently selected from the group consisting of anionic surfactants, cationic surfactants, amphoteric surfactants, non-ionic surfactants and polymeric surfactants.
  • a first surface stabilizer and second surface stabilizer are independently selected from the group consisting of crystallization inhibitors and surfactants.
  • the first surface stabilizer is a crystallization inhibitor and the second surface stabilizer is a surfactant.
  • a first surface stabilizer is an anionic surfactant and a second surface stabilizer is an anionic surfactant.
  • a first surface stabilizer is an anionic surfactant and a second surface stabilizer is a cationic surfactant.
  • a first surface stabilizer is an anionic surfactant and a second surface stabilizer is an amphoteric surfactant.
  • a first surface stabilizer is an anionic surfactant and a second surface stabilizer is a non- ionic surfactant.
  • a first surface stabilizer is an anionic surfactant and a second surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer is a cationic surfactant and a second surface stabilizer is an anionic surfactant.
  • a first surface stabilizer is a cationic surfactant and a second surface stabilizer is a cationic surfactant.
  • a first surface stabilizer is a cationic surfactant and a second surface stabilizer is an amphoteric surfactant.
  • a first surface stabilizer is a cationic surfactant and a second surface stabilizer is a non-ionic surfactant.
  • a first surface stabilizer is a cationic surfactant and a second surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer is an amphoteric surfactant and a second surface stabilizer is an anionic surfactant.
  • a first surface stabilizer is an amphoteric surfactant and a second surface stabilizer is a cationic surfactant.
  • a first surface stabilizer is an amphoteric surfactant and a second surface stabilizer is an amphoteric surfactant.
  • a first surface stabilizer is an amphoteric surfactant and a second surface stabilizer is a non-ionic surfactant.
  • a first surface stabilizer is an amphoteric surfactant and a second surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer is a non-ionic surfactant and a second surface stabilizer is an anionic surfactant.
  • a first surface stabilizer is a non- ionic surfactant and a second surface stabilizer is a cationic surfactant.
  • a first surface stabilizer is a non-ionic surfactant and a second surface stabilizer is am amphoteric surfactant.
  • a first surface stabilizer is a non-ionic surfactant and a second surface stabilizer is a non-ionic surfactant.
  • a first surface stabilizer is a non-ionic surfactant and a second surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer is a polymeric surfactant and a second surface stabilizer is an anionic surfactant.
  • a first surface stabilizer is a polymeric surfactant and a second surface stabilizer is a cationic surfactant.
  • a first surface stabilizer is a polymeric surfactant and a second surface stabilizer is an amphoteric surfactant.
  • a first surface stabilizer is a polymeric surfactant and a second surface stabilizer is a non-ionic surfactant.
  • a first surface stabilizer is a polymeric surfactant and a second surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer is a crystallization inhibitor and a second surface stabilizer is an anionic surfactant.
  • a first surface stabilizer is a crystallization inhibitor and a second surface stabilizer is a cationic surfactant.
  • a first surface stabilizer is a crystallization inhibitor and a second surface stabilizer is am amphoteric surfactant.
  • a first surface stabilizer is a crystallization inhibitor and a second surface stabilizer is a non-ionic surfactant.
  • a first surface stabilizer is a crystallization inhibitor and a second surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer is selected from the group consisting of Pluronic® F108 and Tween® 80 and a second surface stabilizer is selected from the group consisting of Pluronic ® F108, Tween® 80, and SLS.
  • a first surface stabilizer is PVP and a second surface stabilizer is Pluronic® F108.
  • a first surface stabilizer is PVP and a second surface stabilizer is Pluronic® F68.
  • a first surface stabilizer is PVP and a second surface stabilizer is SLS.
  • a first surface stabilizer is Pluronic® F108 and a second surface stabilizer is Tween® 80.
  • a first surface stabilizer is PVP and a second surface stabilizer is Tween® 80.
  • the amount by weight of a first surface stabilizer is from about 0.5% to about3.0 % by weight of the total volume of the formulation. In another embodiment, the amount by weight of a first surface stabilizer is from about 0.5% to about 2.0% by weight of the total volume of the formulation. In yet another embodiment of a formulation of the invention, the amount by weight of a first surface stabilizer is about 0.5% by weight of the total volume of the formulation. In yet another embodiment of a formulation of the present invention, the amount by weight of a first surface stabilizer is about 1.0 % by weight of the total volume of the formulation.
  • the amount by weight of a first surface stabilizer is about 2.0 % by weight of the total volume of the formulation.
  • the amount by weight of a second surface stabilizer is from about 0.1 % to about 3.0 % by weight of the total volume of the formulation.
  • the amount by weight of a second surface stabilizer is about 2.0 % by weight of the total volume of the formulation.
  • amount by weight of a second surface stabilizer is about 1.0 % by weight of the total volume of the formulation.
  • the amount by weight of a second surface stabilizer is about 0.5% by weight of the total volume of the formulation. In still another embodiment of a formulation of the present invention, the amount by weight of a second surface stabilizer is about 0.1% by weight of the total volume of the formulation.
  • a third surface stabilizer is present, wherein the amount by weight of the third surface stabilizer is from about 0.018% to about 1.0 % by weight of the total volume of the formulation. In another embodiment of a formulation of the present invention, the amount by weight of the third surface stabilizer is about 0.018% by weight of the total volume of the formulation.
  • the amount by weight of the third surface stabilizer is about 0.1 % by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the third surface stabilizer is about 0.02% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the third surface stabilizer is about 0.5% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the third surface stabilizer is about 1.0% by weight of the total volume of the formulation.
  • a third surface stabilizer is a surfactant.
  • the third surface stabilizer is selected from the group consisting of Pluronic® F68, benzalkonium chloride, lecithin and SLS.
  • a third surface stabilizer is Pluronic® F68.
  • a third surface stabilizer is benzalkonium chloride.
  • a third surface stabilizer is lecithin.
  • a third surface stabilizer is SLS.
  • the total amount by weight of surface stabilizers in a formulation is about 6% or less, more preferably about 5% or less.
  • a bulking agent is present, wherein the amount by weight of the bulking agent is from about 1.0% to about 10.0 % by weight of the total volume of the formulation. In another embodiment of a formulation of the present invention, the amount by weight of the bulking agent is about 1.0% by weight of the total volume of the formulation. In another embodiment, the amount by weight of the bulking agent is about 5.0% by weight of the total volume of the formulation. In another embodiment, the amount by weight of the bulking agent is about 10.0% by weight of the total volume of the formulation.
  • a bulking agent is present, the bulking agent selected from the group consisting of trehalose, mannitol and PEG400.
  • the bulking agent is trehalose.
  • the bulking agent is mannitol.
  • the bulking agent is PEG400.
  • the formulation consists essentially of a compound, a carrier, a first surface stabilizer and a second surface stabilizer, as previously defined herein.
  • the formulation consists essentially of a compound, a carrier, a first surface stabilizer, a second surface stabilizer and a third surface stabilizer, as previously defined herein.
  • the formulation consists essentially of a compound, a carrier, a first surface stabilizer, a second surface stabilizer and a bulking agent, as previously defined herein.
  • the compound nanoparticles can be made using several different methods, including, for example, milling, precipitation and high pressure homogenization. Exemplary methods of making compound nanoparticles are described in U.S. Patent No. 5,145, 684, the entire content of which is hereby incorporated by reference.
  • the optimal effective average particle size of the invention can be obtained by controlling the process of particle size reduction, such as controlling the milling time and the amount of surface stabilizer added. Crystal growth and particle aggregation can also be minimized by milling or precipitating the composition under colder temperatures, and by storing the final composition at colder temperatures.
  • Milling of compound in aqueous solution to obtain a nanoparticulate dispersion comprises dispersing compound in water, followed by applying mechanical means in the presence of grinding media to reduce the particle size of the compound to the desired effective average particle size, the optimal sizes as provided in other embodiments herein.
  • the compound can be effectively reduced in size optionally in the presence of one or more surface stabilizers.
  • the compound can optionally be contacted with a surface stabilizer or surface stabilizers after attrition.
  • the compound is milled in the presence of at least one surface stabilizer, more preferable in the presence of at least two stabilizers; or the compound is contacted with at least one, more preferably at least two surface stabilizers, subsequent to attrition.
  • Other compounds such as a bulking agent, can be added to the compound/surface stabilizer mixture during the size reduction process.
  • Dispersions can be manufactured continuously or in a batch mode.
  • the resultant nanoparticulate drug dispersion can be utilized in solid or liquid dosage formulations.
  • the nanoparticulate dispersion may be utilized in intramuscular depot formulations suitable for injection.
  • Exemplary useful mills include low energy mills, such as a roller mill, attritor mill, vibratory mill and ball mill, and high energy mills, such as Dyno mills, Netzsch mills, DC mills, and Planetary mills.
  • Media mills include sand ills and bead mills.
  • the compound is placed into a reservoir along with a dispersion medium (for example, water) and at least two surface stabilizers.
  • the mixture is recirculated through a chamber containing media and a rotating shaft/impeller.
  • the rotating shaft agitates the media which subjects the compound to impacting and sheer forces, thereby reducing particle size. 2. Grinding Media
  • Exemplary grinding media comprises particles that are substantially spherical in shape, such as beads, consisting essentially of polymeric resin.
  • the grinding media comprises a core having a coating of a polymeric resin adhered thereon.
  • Other examples of grinding media comprise essentially spherical particles comprising glass, metal oxide, or ceramic.
  • suitable polymeric resins are chemically and physically inert, substantially free of metals, solvent, and monomers, and of sufficient hardness and friability to enable them to avoid being chipped or crushed during grinding.
  • Suitable polymeric resins include, without limitation: crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene; styrene copolymers; polycarbonates; polyacetals, for example, Delrin® (E.I. du Pont de Nemours and Co.); vinyl chloride polymers and copolymers; polyurethanes; polyamides; poly(tetrafluoroethylenes), for example, Teflon® (E.I.
  • du Pont de Nemours and Co. and other fluoropolymers; high density polyethylenes; polypropylenes; cellulose ethers and esters such as cellulose acetate; polyhydroxymethacrylate; polyhydroxyethyl acrylate; and silicone-containing polymers such as polysiloxanes.
  • the polymer can be biodegradable.
  • biodegradable polymers include poly(lactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacylate), poly(imino carbonates), poly(N- acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes).
  • contamination from the media itself advantageously can metabolize in vivo into biologically acceptable products that can be eliminated from the body.
  • the grinding media preferably ranges in size from about 10 ⁇ m to about 3 mm.
  • exemplary grinding media is from about 20 ⁇ m to about 2 mm.
  • exemplary grinding media is from about 30 ⁇ m to about 1 mm in size.
  • the grinding media is about 500 ⁇ m in size.
  • the polymeric resin can have a density from about 0.8 to about 3.0 g/ml.
  • the particles are made continuously.
  • Such a method comprises continuously introducing compound into a milling chamber, contacting the compound with grinding media while in the chamber to reduce the compound particle size, and continuously removing the nanoparticulate compound from the milling chamber.
  • the grinding media is separated from the milled nanoparticulate compound using conventional separation techniques in a secondary process, including, without limitation, simple filtration, sieving through a mesh filter or screen, and the like. Other separation techniques such as centrifugation may also be employed.
  • Another method of forming the desired nanoparticulate dispersion is by microprecipitation.
  • This is a method of preparing stable dispersions of drugs optionally in the presence of one or more surface stabilizers and optionally one or more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities.
  • An exemplary method comprises:
  • the formulation is preferably precipitated after addition to a solution of at least one, more preferably at least two, surface stabilizers.
  • the method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.
  • the resultant nanoparticulate drug dispersion can be utilized in solid or liquid dosage formulations. In another embodiment, the nanoparticulate dispersion may be utilized in intramuscular depot formulations suitable for injection.
  • the geometry of the Interaction Chamber produces powerful forces of sheer, impact and cavitation which reduce particle size.
  • the pressurized mixture is split into two streams and accelerated to extremely high velocities.
  • the formed jets are then directed toward each other and collide in the interaction zone.
  • the resulting product has very fine and uniform particle size. 5.
  • some of the processing is dependent upon the method of particle size reduction and/or method of sterilization.
  • media conditioning is not required for a milling method that does not use media.
  • terminal sterilization is not feasible due to chemical and/or physical instability, aseptic processing can be used. Terminal sterilization can be by steam sterilization or by high energy irradiation of the product.
  • the conditions that can be treated in accordance with the present invention include psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioral disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioral disturbances in mental retardation and autism, Tourette's syndrome, bipolar disorder (for example bipolar mania, bipolar depression, or effecting mood stabilization in bipolar disorder), depression and anxiety.
  • psychosis schizophrenia, schizoaffective disorders, non-schizophrenic psychoses
  • behavioral disturbances associated with neurodegenerative disorders e.g. in dementia, behavioral disturbances in mental retardation and autism, Tourette's syndrome
  • bipolar disorder for example bipolar mania, bipolar depression, or effecting mood stabilization in bipolar disorder
  • depression and anxiety for example bipolar mania, bipolar depression and anxiety.
  • a formulation described in this specification is administered in an amount effective to treat conditions listed herein.
  • the depot formulations of the present invention are administered by injection, whether subcutaneously or intramuscularly, and in a dose effective for the treatment intended.
  • Therapeutically effective doses of the compounds required to prevent or arrest the progress of or to treat the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
  • An effective dose for injection of a formulation of the invention can be generally determined by a physician of ordinary skill in the art.
  • the effective dose can be determined taking into consideration factors know to those of skill in the art, such as the indication being treated, the weight of the patient, and the duration of treatment (e.g. days or weeks) desired.
  • the percentage of drug present in the formulation is also a factor.
  • An example of an effective dose for injection of a formulation of the present invention is from about 0.1 ml to about 2.5 ml injected once every 1 , 2, 3 or 4 weeks.
  • the dose for injection is about 2 ml or less, for example from about 1 ml to about 2 ml.
  • the injection volume is 2 ml, injected once every 1 , 2, 3 or 4 weeks.
  • the present invention comprises methods for the preparation of a formulation (or "medicament') comprising the Formulations embodied in Formulations 1-4, and subformulations thereof, in combination with one or more pharmaceutically-acceptable carriers.
  • at least one, preferably at least two surface stabilizers are adsorbed on to the surface of the compound nanoparticles in an amount effective to maintain nanoparticle size for use in treating conditions including, without limitation, psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioral disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioral disturbances in mental retardation and autism, Tourette's syndrome, bipolar disorder (for example bipolar mania, bipolar depression, or effecting mood stabilization in bipolar disorder), depression and anxiety.
  • bipolar disorder for example bipolar mania, bipolar depression, or effecting mood stabilization in bipolar disorder
  • a coarse suspension was prepared by placing 8.86 gm of ziprasidone free base in a 100 ml milling chamber with 48.90 gm of milling media (500 micron . polystyrene beads).
  • the above suspension after milling was free flowing and did not show any large crystals under the microscope at 400X and dispersed particles could not be seen individually due to the rapid Brownian motion.
  • the effective diameter of the 21 % ziprasidone free base nanosuspension was 235 nm.
  • a 21% ziprasidone free base coarse suspension was prepared in 2.5% aqueous solution of Pluronic® F108.
  • This suspension was diluted 1 :1 v/v with water to result in 10.5% ziprasidone free base suspension with 1.25% of Pluronic® F108 in water.
  • the suspension was milled in a 100 ml milling chamber with milling media (500 micron polystyrene beads) at 5500 RPM.
  • the effective diameter of the 10.5% ziprasidone free base nanosuspension was 181 nm.
  • a coarse suspension was prepared by placing 9.69 gm of ziprasidone hydrochloride in a 100 ml milling chamber with 48.96 gm of milling media (500 micron polystyrene beads).
  • the effective diameter of the 23% ziprasidone hydrochloride nanosuspension was 117 nm.
  • Preparation of Formulation F A coarse suspension was prepared by placing 11.78 gm of ziprasidone mesylate in a 100 ml milling chamber with 48.89 gm of milling media (500 micron polystyrene beads).
  • the effective diameter of the 28% ziprasidone mesylate nanosuspension was 406 nm.
  • a coarse suspension was prepared by placing 8.85 gm of ziprasidone free base in the 100 ml milling chamber with 48.89 gm of milling media (500 micron polystyrene beads).
  • a coarse suspension was prepared by placing 8.87 gm of ziprasidone free base in the 100 ml milling chamber with 48.9 gm of milling media (500 micron polystyrene beads).
  • Example 7 The filtered suspension of Example 7 was filled (3 ml) into flint vials.
  • the vials were sealed with a rubber stopper and an aluminum seal was crimped on the stopper.
  • the filled vials were sterilized for 15 min at 121°C in a steam sterilizer.
  • the suspension after sterilization was characterized and particle size measured by light scattering.
  • the filled vials were stored at 5°C and sampled at various times to determine particle size and stability of the suspension.
  • the following table shows particle size stability of Formulation G during autoclaving and upon storage of the sterilized formulation.
  • Table D-4 Effective Particle Diameter of Formulation G after Autoclaving and upon Storage at 5°C.
  • Example 8 The filtered suspension of Example 8 was filled (3 ml) into flint vials. The vials were sealed with a rubber stopper and an aluminum seal was crimped on the stopper. The filled vials were sterilized for 15 min at 121 0 C in a steam sterilizer.
  • the suspension after sterilization was characterized and particle size measured by light scattering.
  • the filled vials were stored at 5°C and sampled at various times to determine particle size and stability of the suspension.
  • the following table shows particle size stability of Formulation H during autoclaving and upon storage of the sterilized formulation.
  • Table D-5 Effective Particle Diameter of Formulation H after Autoclaving and upon Storage at 5 0 C.
  • the combination of two or more surface stabilizers provide enhanced surface stability and improve the ability of the crystal to maintain its nanoparticulate size without aggregation.
  • the addition of a different, second surface stabilizer may allow for the reduction in total amount of surface stabilizers by % w/v, which supports a synergistic interaction between surface stabilizers.
  • a coarse suspension was prepared by placing 21.92 gm of ziprasidone free base in the 100 ml milling chamber with 38.42 gm of milling media (500 micron polystyrene beads).
  • the filtered suspension was filled (2.5 ml) into flint vials.
  • the vials were sealed with a rubber stopper and an aluminum seal was crimped on the stopper.
  • the filled vials were sterilized for 15 min at 121 0 C in a steam sterilizer.
  • the suspension after sterilization was characterized and particle size measured by light scattering.
  • the following table shows particle size stability of the 42% ziprasidone free base formulation after milling and following autoclaving.
  • Table D-7 Mean Particle Size of 42% Formulation I After Milling and
  • Formulation J was prepared as described in example 15.
  • the filtered suspension was filled (3 ml) into flint vials.
  • the vials were sealed with a rubber stopper and an aluminum seal was crimped on the stopper.
  • the filled vials were sterilized for 15 min at 121 0 C in a steam sterilizer.
  • the suspension after sterilization was characterized and particle size measured by light diffraction.
  • the filled vials were stored at 5, 25, and 40 0 C and sampled at various times to determine particle size and stability of the suspension.
  • Table D-8 Mean Particle Size of Formulation J after Autoclaving and Upon Storage at 5, 25 and 40°C.
  • a coarse suspension was prepared by placing pre-ground 17.71 gm ziprasidone freebase in 250 mL bottle with 8.4 mL of each, 10%w/v Pluronic F108 and 10%w/v Tween 80 and 55.6 mL of water. The suspension was placed in a cooling bath set to 5°C. The high pressure homogenizer (Manufacturer Avestin, Inc.) was cleaned and primed with water at full open setting. The suspension was pumped for three minutes under the full open condition of the homogenizer during which time it flowed smoothly. The pressure drop across the gap was then slowly increased to 10,000 psi, and held for 5 minutes. The pressure drop across the gap was then increased to15,000 psi, and was held here for 22 minutes.
  • Manufacturer Avestin, Inc. Manufacturer Avestin, Inc.
  • Table D-9 Particle size stability of autoclaved 21 % ziprasidone free base nanosuspension prepared by high pressure homogenization.
  • the 21%w/v Ziprasidone freebase nanosuspension was prepared by methods described in examples 7 and 8. Batch of 27%w/v Trehalose, 1%w/v F108, 1 %w/v Tween 80, and 0.5%w/v Lecithin in water was used as diluent to prepare the samples for lyophilization. The formulation and diluent were combined in a ratio of 3 volumes of diluent to 1 volume of 21 % formulation and were gently mixed. This resultant suspension was filled using a 0.5 mL fill volume into 5 mL and 10 mL glass vials and stoppered at the lyophilization position. These vials were then placed into the FTS LyoStar freeze-drying unit, and the following thermal program was run: 1 ) Shelves were cooled at 0.2 °C/min (for 300 min) to -40 0 C and held here for 120 min.
  • Shelves were warmed at 1 °C/min (for 20 min) to 30 0 C and 150 mTorr and held for 720 min.
  • the freeze-drying cycle was manually stopped, and the vials were stoppered and crimped. They were then placed in the refrigerator for storage.
  • the dry cake in the vials were reconstituted with the same volume as the initial fill with either 0.5 mL of water or 0.5 mL of 1%w/v F108, 1 %w/v Tween ⁇ O, 0.5%w/v Lecithin in water (the formulation vehicle). These vials were swirled, upon which the cake wetted and reconstituted into a milky white suspension easily.

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